The aminolysis of 6-chloropyrimidine and 2-amino-6-chloropyrimidine has been examined by-using density functional theory. Relative to the aminolysis of 6-chloropyrimidine, the addition of an electron-donating NH2 group to C-2 increases the barrier to aminolysis, indicating that the third hydrogen bond does not play a catalytic role but introduces additional rigidity into the system. However, the computations suggest that there is an interesting correlation between the barrier to aminolysis and the proton affinity of the species that interacts with the incoming NH3. To extend the range of proton affinities, the aminolysis of 6-chloropyrimidine was examined by using fluoro, imine, and thioketo derivatives of the uracil-derived bases. The proton affinity of the moiety that hydrogen bonds with NH3 is decreased by fluoro substitution, and thus the aminolysis barriers are increased. Similarly, imine substitution enhances the PA of the moiety, which is reflected in a decrease in the aminolysis barriers. The same correlation exists for the thioketo-derived bases, whose PA are intermediate between the fluoro and imine derivatives. Thus, the aminolysis of 6-chloropryimidine and 2-amino-6-chloropyrimidine demonstrates the importance of a well-chosen proton acceptor and the catalytic possibilities associated with the formation of multiple hydrogen bonds.